PROJECT SUMMARY/ABSTRACT We have identified somatic gene recombination (SGR) in neurons of the human brain, with particular relevance to sporadic Alzheimer?s disease (SAD) (Nature 563, 639-645 (2018)). This discovery represents a new and functionally significant aspect of genomic mosaicism (eLife;4:e05116 (2015)) that has genuine therapeutic potential through newly identified molecular targets. Indeed, we found that SGR, acting on the AD gene for Amyloid Precursor Protein (APP), produces thousands of distinct forms of APP, some of which are enriched in or unique to AD. The APP gene variations related to AD that were analyzed thus far include copy number variations (CNVs) and at least 11 single-nucleotide variations (SNVs) that were previously reported as pathogenic in familial AD, yet that arose somatically and mosaically in SAD; these variations were absent from non-diseased neurons. SGR utilizes reverse transcriptase (RT) activity on transcribed RNAs that, combined with DNA strand-breaks and APP gene transcription, produce double-stranded DNA that is retro-inserted back into the genome to form ?genomic cDNAs? (gencDNAs). These published data contribute to the scientific foundation on which the current proposal will build, to test the hypothesis that altered SGR, involving brain- specific reverse transcriptases, functionally contributes to AD and affects multiple genes, providing novel targets for AD therapies. Postmortem IRB-approved and de-identified brain samples from validated AD donors of both sexes will be compared to non-diseased controls, while IACUC-approved animal experiments will model SGR and its AD-relevant endpoints. Three Aims will be pursued over 5 years. Aim 1 will define the molecular neurobiology of APP gencDNA diversity and identify new SGR genes enhanced in AD brains. Aim 2 will determine expression and function of SGR genes in AD brain and model systems. Aim 3 will identify genes responsible for RT SGR activity within normal and AD brains. This proposal will thus open new vistas into AD via novel SGR mechanisms and will identify new therapeutic targets for the treatment of AD.